Paneth cells are highly specialized epithelial cells located in the small intestine that function to regulate the composition of the intestinal flora, the host microvasculature, the normal injury and repair mechanisms of the intestinal epithelial layer, and levels of intestinal inflammation. While Paneth cells develop early in human gestation, they do not become immune competent until closer to term gestation, leaving preterm infants deficient in normal Paneth cell biology during the greatest window of susceptibility to develop NEC. Infants who have developed NEC have decreased Paneth cell numbers compared to age-matched controls, and ablation of murine Paneth cells results in a NEC-like phenotype. This chapter aims to provide an understanding of the role of the Paneth cell in the development of NEC.